Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters

• Published in: International journal of cancer 2013-09, Vol.133 (6), p.1479-1488
• Main Authors: Hasegawa, Naoyuki, Abei, Masato, Yokoyama, Kazunari K., Fukuda, Kuniaki, Seo, Emiko, Kawashima, Rei, Nakano, Yuri, Yamada, Takeshi, Nakade, Koji, Hamada, Hirofumi, Obata, Yuichi, Hyodo, Ichinosuke
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenovirus; Animals; Antineoplastic agents; Biological and medical sciences; Cancer; Cancer therapies; Cell Line, Tumor; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); conditionally replicative adenovirus; Cricetinae; Cyclophosphamide - therapeutic use; Female; Fluorouracil - therapeutic use; Gene therapy; Immunocompetence; Immunology; immunosuppression; Medical research; Medical sciences; Mesocricetus; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); oncolytic virus; Oncolytic Viruses - genetics; pancreas cancer; Pancreatic Neoplasms - therapy; Pentosyltransferases - genetics; Pharmacology. Drug treatments; Rodents; Transduction, Genetic; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28132

Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5‐fluorouracil (5‐FU), in immunodeficient, Ad‐nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5‐FU therapy and of its combination with CP for syngenic HaP‐T1 pancreatic cancers in immunocompetent, Ad‐permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5‐FU in HaP‐T1 cells in vitro. I.t. AxE1CAUP/5‐FU treatment inhibited the growth of subcutaneous HaP‐T1 allografts. The combination with high‐dose CP inhibited serum Ad‐neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5‐FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically‐approved, intermediate‐dose CP also enhanced the efficacy of i.t. AxE1CAUP/5‐FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad‐permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV‐mediated gene therapy. What's new? Oncolytic viruses offer great promise as cancer therapeutics, but host antiviral immunity must be overcome for their efficacy. This study demonstrates the efficacy and safety of an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase and further enhancement of this efficacy by a high‐dose or clinically‐approved safe dose of the immunosuppressive agent cyclophosphamide (CP) in Syrian hamsters with or without preexisting immunity. This is the first study demonstrating enhancement by CP of the efficacy of an OAd armed with a therapeutic gene in Ad‐permissive immunocompetent animals, indicating the ability of CP to overcome the hurdle of antiviral immunity for effective virus‐ge